Methylmalonic acidaemia

M12. Morrow, G., and Burkel, G. M., Long term management of a patient with vitamin B12-responsive methylmalonic acidaemia. J. Pediatr. 93, 425-426 (1980). 

Table 41.7 Methionine-, threonine-, valine- and Isoleuolne-free dietary preparations for the management of methylmalonic acidaemia and proprionio aoidaemia ...

Richard E, et al. Methylmalonic acidaemia leads to increased production of reactive oxygen species and induction of apoptosis through the mitochondrial/ caspase pathway. J Pathol. 2007 213(4) 453-61. 

Nagarajan S, et al. Management of methylmalonic acidaemia by combined liver-kidney transplantation. J Inherit Metab Dis. 2005 28(4) 517-24. 

Wasserstein MP, et al. Successful pregnancy in severe methylmalonic acidaemia. J Inherit Metab Dis. 1999 22(7) 788-94. 

Microdetermination of Methylmalonic Acid and Other Short-Chain Dicarb-oxylic Acids by Gas Chromatography Use of Prenatal Diagnosis of Methylmalonic Acidaemia and in Studies of Isovaleric Acidaemia Clin. Chim. Acta 68(2) 127-140 (1976) CA 85 1974n... 

Three conditions show certain similarities and can be considered together ketotic glycinaemia [97], non-ketotic glycinaemia [98] and methylmalonic acidaemia [99]. In all three the concentration of glycine in the blood is from 12 to 70 mg per 100 ml (normal < 2 mg per 100 ml) and the concentration of glycine in the urine is from 4,000 to 8,000 mg... 

In vitamin Bj2 deficiency, methylmalonic acid is excreted in the urine [103]. However, there also exists methylmalonic acidaemia as an inborn error of metabolism, distinct from vitamin B12 deficiency, with higher concentrations of methylmalonic acid in blood and urine [99, 104]. The blood and urine contain excess glycine—up to 12 mg per 100 ml blood and up to 4,000 mg per g creatinine in urine [99, 104-107]. The site of the metabolic block is reaction 4, methylmalonic acidaemia is caused by lack or inactivity of methylmalonyl-CoA mutase [108, 109]. Although there is no deficiency of vitamin Bi2, giving large doses causes a decrease in methylmalonic acid excretion in some cases (Bi2 i esponsive) [110]. Liver biopsy specimens from Bi2 i esponsive patients converted methyl-malonyl-CoA to succinyl-CoA at 10% of the normal rate, rising to normal with added Bj2 cofactor specimens from Bi2-unresponsive patients did not convert any methyl-malonyl-CoA to succinyl-CoA with or without added Bj2 cofactor [111]. 

In all three conditions the first signs commonly appear within 48 h of birth. The infant ceases to suck, becomes drowsy and may have convulsions. At this time marked ketosis appears in ketotic glycinaemia and methylmalonic acidaemia. Most affected infants go rapidly downhill and die within a few days or weeks of birth. In some cases the onset of symptoms is later, up to four months of age, and the disease runs a slower course with survival for several years. The survivors show mental and physical retardation (I.Q. seizures, E.E.G. abnormalities,... 

In methylmalonic acidaemia, leucine, valine, isoleucine, methionine and threonine are toxic and all other aimino acids (including glycine) are non-toxic, as is found in ketotic glycinaemia [99]. There is no explanation of the effect of leucine. 

Treatment of both ketotic glycinaemia and methylmalonic acidaemia is with a diet low in the five toxic amino acids. On this treatment children survive and thrive, though it is too soon for assessment of the effect on the G.N.S. 

Chalmers, R.A., Lawson, A.M. and Watts, R.W.E. (1974a), Studies on the urinary acidic metabolite excreted by patients with )8-methylcrotonylglycinuria, propionic acidaemia, and methylmalonic acidaemia, using gas-liquid chromatography and mass spectrometry. Clin. Chim. Acta, 52,43. 

Ampola, M.G., Mahoney, M.J., Nakamura, E. and Tanaka, K. (1975), Prenatal therapy of a patient with vitamin-Bi2-responsive methylmalonic acidaemia. N. Engl. J. Med., 293,314. 

Duran, M., Ketting, D., Wadman, S.K., Trijbels, J.M.F., Bakkeren, J.A.J.M. and Waelkens, J. J. J. (1973), Propionic acid, an artefact which can leave methylmalonic acidaemia undiscovered. Clin. Chim. Acta, 49,177. 

Lindblad, B., Lindblad, B.S., Olin, P., Svanberg, B. and Zetterstrom, R. (1968) Methylmalonic acidaemia. Acta Paediatr. Scand., 57,417. 

Rosenberg, L.E. (1979), The inherited methylmalonic acidaemias A model system for the study of vitamin metabolism and apoenzyme-coenzyme interactions. The Milner Lecture Proc. 17th Anna. Meet. Soc. Study Inborn Errors Metab. Leeds, September, 1979. In the press, 1981. 

Stokke, O., Eldjam, L., Norum, K.R., Steen-Johnsen, J. and Halvorsen, S. (1967) Methylmalonic acidaemia. A new inborn error of metabolism which may cause fatal acidosis in the neonatal period. Scand. J. Clin. Lab. Invest., 20,313. 

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